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Objectives: High-mobility group box-1 (HMGB1) and aberrant mitochondrial fission mediated by excessive activation of GTPase dynamin-related protein 1 (Drp1) have been found to be elevated in patients with pulmonary arterial hypertension (PAH) and critically implicated in PAH pathogenesis. However, it remains unknown whether Drp1-mediated mitochondrial fission and which downstream targets of mitochondrial fission mediate HMGB1-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration leading to vascular remodelling in PAH. This study aims to address these issues., Methods: Primary cultured PASMCs were obtained from male Sprague-Dawley (SD) rats. We detected RNA levels by qRT-PCR, protein levels by Western blotting, cell proliferation by Cell Counting Kit-8 (CCK-8) and EdU incorporation assays, migration by wound healing and transwell assays. SD rats were injected with monocrotaline (MCT) to establish PAH. Hemodynamic parameters were measured by closed-chest right heart catheterization., Results: HMGB1 increased Drp1 phosphorylation and Drp1-dependent mitochondrial fragmentation through extracellular signal-regulated kinases 1/2 (ERK1/2) signalling activation, and subsequently triggered autophagy activation, which further led to bone morphogenetic protein receptor 2 (BMPR2) lysosomal degradation and inhibitor of DNA binding 1 (Id1) downregulation, and eventually promoted PASMCs proliferation/migration. Inhibition of ERK1/2 cascade, knockdown of Drp1 or suppression of autophagy restored HMGB1-induced reductions of BMPR2 and Id1, and diminished HMGB1-induced PASMCs proliferation/migration. In addition, pharmacological inhibition of HMGB1 by glycyrrhizin, suppression of mitochondrial fission by Mdivi-1 or blockage of autophagy by chloroquine prevented PAH development in MCT-induced rats PAH model., Conclusions: HMGB1 promotes PASMCs proliferation/migration and pulmonary vascular remodelling by activating ERK1/2/Drp1/Autophagy/BMPR2/Id1 axis, suggesting that this cascade might be a potential novel target for management of PAH., (© 2021 The Authors. Cell Proliferation published by John Wiley & Sons Ltd.)

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common chronic liver diseases in the world. It has been reported that epigallocatechin-3-gallate (EGCG) plays important biological and pharmacological roles in mammalian cells. Nevertheless, the mechanism underlying the beneficial effect of EGCG on the progression of NAFLD has not been fully elucidated. In the present study, the mechanisms of action of EGCG on the growth, apoptosis, and autophagy were examined using oleic acid- (OA-) treated liver cells and the high-fat diet- (HFD-) induced NAFLD mouse model. Administration of EGCG promoted the growth of OA-treated liver cells. EGCG could reduce mitochondrial-dependent apoptosis and increase autophagy possibly via the reactive oxygen species- (ROS-) mediated mitogen-activated protein kinase (MAPK) pathway in OA-treated liver cells. In line with in vitro findings, our in vivo study verified that treatment with EGCG attenuated HFD-induced NAFLD through reduction of apoptosis and promotion of autophagy. EGCG can alleviate HFD-induced NAFLD possibly by decreasing apoptosis and increasing autophagy via the ROS/MAPK pathway. EGCG may be a promising agent for the treatment of NAFLD., Competing Interests: The authors declare that there is no conflict of interests., (Copyright © 2021 Dongdong Wu et al.)

It has been shown that sphingosine-1-phosphate (S1P) is elevated in patients with pulmonary arterial hypertension (PAH) and promotes the proliferation of pulmonary artery smooth muscle cells (PASMCs). Meanwhile, S1P has been found to induce the activation of autophagy in several types of human diseases including cancers. However, it is still unclear whether activation of autophagy mediates S1P-induced PASMCs proliferation, and detailed mechanisms responsible for these processes are indefinite. The aims of this study are to address these issues. S1P dose- and time-dependently reduced the expression of E-cadherin/CDH1 and stimulated PASMCs proliferation; this was accompanied with the elevation of TNF receptor-associated factor 2 (TRAF2), up-regulation and ubiquitination of BECN1 and the activation of autophagy. Prior silencing TRAF2 or BECN1 using siRNA or pre-incubation of cells with autophagy inhibitor chloroquine phosphate (CQ) suppressed S1P-induced autophagy activation and subsequent CDH1 degradation and further PASMCs proliferation. Taken together, our study indicates that S1P promotes the activation of autophagy by accelerating TRAF2-mediated BECN1 up-regulation and ubiquitination, which in turn results in CDH1 reduction and contributes to PASMCs proliferation., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ulcerative colitis (UC) is a recurrent intestinal inflammatory disease. Slit2, a secreted protein, interacts with its receptor Robo1 to regulate the differentiation of intestinal stem cells and participate in inflammation and tumor development. However, whether Slit2/Robo1involved in the pathogenesis of UC is not known. We investigated Slit2/Robo1-mediated UC using a dextran sodium sulfate (DSS)-induced model. Eight-week-old male Slit2-Tg (Slit2 transgene) mice, Robo1/2 +/- (Robo1 +/- Robo2 +/- ) mice, and their WT littermates were allocated into two groups: (I) control group (n=10), of mice fed a normal diet and tap water and (II) DSS group (n=10), of mice fed a normal diet and drinking water with 2% DSS for 7 days. Colon tissues were collected and analyzed by qPCR, immunohistochemistry, western blot, and immunofluorescence. Slit2-Tg DSS mice showed less body weight loss, less blood in the stool, and less viscous stool compared to those of WT Slit DSS mice. Robo1/2 +/- DSS mice displayed a heavier degree of blood in the stool and a more apparent viscosity of the stool compared to those of WT Robo1/2 DSS mice. Slit2 overexpression maintained Lgr5 + stem cell proliferation in the crypt after DSS treatment, significantly increased the LC3II/I ratio, and slightly stimulated p62 expression in the crypt compared to those of DSS-induced WT Slit mice. Robo1/2 partial knockout reduced the number of Lgr5 + stem cells, decreased the LC3II/I ratio, and markedly increased p62 expression in the crypt compare to those of DSS-treated WT Robo1/2 mice. Our findings suggest that Slit2/Robo1 mediates DSS-induced UC probably by activating the autophagy of Lgr5 + stem cells., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Autophagy is a self-degrading process. Previously, we showed that insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) is a novel transforming growth factor β1 (TGFβ1)-interacting factor in liver fibrosis; the role of TGFβ1-mediated autophagy in hepatic stellate cells (HSCs) activation has been investigated. However, whether autophagy is regulated by IGFBPrP1 remains unknown., Aims: We investigated the interactions among IGFBPrP1, autophagy, and activation of primary rat HSCs., Methods: Primary HSCs were separated from Sprague Dawley rats by two-step enzymatic digestion, and then, we overexpressed or inhibited IGFBPrP1 expression in HSCs under serum-starved condition. Autophagy inducer rapamycin or inhibitor 3-methyladenine (3MA) was used to assess the relationship between autophagy and HSCs activation., Results: We observed the expression of activation marker α-SMA and autophagy markers such as LC3B and Beclin1, which were significantly increased in HSCs treated with adenovirus vector harboring the IGFBPrP1 gene (AdIGFBPrP1) compared to cells cultured under serum-starved. In comparison, HSCs treated with shIGFBPrP1 showed opposite results. Furthermore, HSCs activation and autophagy increased when cells were treated with rapamycin, whereas opposite results were obtained when cells were treated with 3MA. AdIGFBPrP1 treatment downregulated the phosphorylation of Akt and mTOR., Conclusion: Autophagy was induced in IGFBPrP1-treated primary HSCs, and IGFBPrP1-induced autophagy promoted the activation of HSCs and extracellular matrix expression, the underlying mechanism of which may involve the phosphatidylinositide 3-kinase/Akt/mTOR signaling pathway.

Aims: Insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) promotes hepatic stellate cell (HSC) autophagy and activation. However, the underlying mechanism remains unknown. Noncoding RNAs (ncRNAs) including long noncoding RNAs (lncRNAs) and microRNAs (miRNAs), have received increasing attention. We aimed to investigate the roles of the lncRNA nuclear enriched abundant transcript 1 (NEAT1), miR-29b, and autophagy related protein 9a (Atg9a), and their relationships with each other during IGFBPrP1-induced HSC autophagy and activation., Main Methods: Levels of NEAT1, miR-29b, Atg9a, and autophagy were detected in adenovirus-mediated IGFBPrP1 (AdIGFBPrP1)-treated mouse liver tissue and immortalized mouse hepatic stellate cell line JS1 transfected with either AdIGFBPrP1 or siIGFBPrP1. In AdIGFBPrP1-treated JS1 cells, autophagy and activation were detected after altering NEAT1, miR-29b, or Atg9a levels. In AdIGFBPrP1-treated JS1 cells, relationships among NEAT1, miR-29b, and Atg9a were explored using dual-luciferase reporter assays, Western blot, qRT-PCR, and immunofluorescence., Key Findings: IGFBPrP1 increased levels of NEAT1, Atg9a, and autophagy while decreasing the level of miR-29b in mouse liver tissues and mouse HSCs. Moreover, NEAT1 increased HSC autophagy and activation while miR-29b decreased both processes. Atg9a also participated in IGFBPrP1-induced HSC autophagy and activation. Importantly, NEAT1, miR-29b, and Atg9a formed a NEAT1/miR-29b/Atg9a regulatory axis for IGFBPrP1-induced HSC autophagy and activation., Significance: Our study unveiled the new NEAT1/miR-29b/Atg9a regulatory axis involved in IGFBPrP1-induced mouse HSC autophagy and activation. The study thus provides new insights in the pathogenesis and potential therapeutic strategies of liver fibrosis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: It has been shown that activation of autophagy is involved in the development of pulmonary arterial hypertension (PAH). Meanwhile, activation of nuclear factor-kappaB (NF-κB) has been found to induce autophagy in several types of human diseases including cancer and cardiac diseases. However, it is still unknown whether NF-κB mediates autophagy activation in PAH, and whether activation of adenosine monophosphate-activated protein kinase (AMPK) benefits PAH by modulation of NF-κB and autophagy., Main Methods: Rat models of PAH were established by intraperitoneally injection of monocrotaline (MCT). The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and percentage of medial wall thickness (%MT) were performed to evaluate the development of PAH. The translocation of NF-κB p65 from cytosol to nucleus, the protein levels of LC3A, LC3B, and RND3 were determined by immunoblotting. Metformin was used to activate AMPK., Key Findings: NF-κB and autophagy were significantly activated in MCT-induced PAH rats, this was accompanied with the reduction of RND3. Pharmacological inhibition of NF-κB suppressed MCT-induced activation of autophagy and down-regulation of RND3 expression and reduced RVSP, RVHI, and %MT in MCT-induced PAH rats. In addition, activation of AMPK by metformin suppressed NF-κB-mediated autophagy activation and down-regulation of RND3 and therefore reduced RVSP, RVHI, and %MT in MCT-induced PAH., Significance: NF-κB-induced autophagy activation and consequent down-regulation of RND3 contributes to the development of PAH in MCT-treated rats. Activation of AMPK prevents the development of PAH by targeting on NF-κB to suppress autophagy and vascular remodeling., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The article titled "Retraction Note: Insulin-Like Growth Factor Binding Protein-Related Protein 1 Activates Primary Hepatic Stellate Cells via Autophagy Regulated by the PI3K/Akt/mTOR Signaling Pathway" has been retracted by the Editor-in-Chief of Digestive Diseases & Sciences. Concerns were raised about the images presented in the figures, including issues of duplication, similarity, and artifacts. The Editor-in-Chief no longer has confidence in the data presented, and all authors agree with the retraction. Springer Nature, the publisher, remains neutral regarding jurisdictional claims and institutional affiliations. [Extracted from the article]

Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. Hydrogen sulfide (H2S) is involved in a wide range of physiological and pathological processes. Nevertheless, the mechanism of action of H2S in NAFLD development has not been fully clarified. Here, the reduced level of H2S was observed in liver cells treated with oleic acid (OA). Administration of H2S increased the proliferation of OA-treated cells. The results showed that H2S decreased apoptosis and promoted autophagy through reactive oxygen species (ROS)-mediated phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade in OA-treated cells. In addition, administration of H2S relieved high-fat diet (HFD)-induced NAFLD via inhibition of apoptosis and promotion of autophagy. These findings suggest that H2S could ameliorate HFD-induced NAFLD by regulating apoptosis and autophagy through ROS/PI3K/AKT/mTOR signaling pathway. Novel H2S-releasing donors may have therapeutic potential for the treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the three major malignant tumors in the world. The major treatments currently recommended for it are surgery, radiotherapy, and chemotherapy, all of which are frequently accompanied by a poor prognosis and high recurrence rate. To limit cell proliferation and metastasis, trigger cell apoptosis, and regulate tumor microenvironment (TME), researchers are focusing attention on investigating highly effective and non-toxic natural medicines. According to the research reported in 89 pieces of related literature, between 2018 and 2021, specialists extracted 48 different types of polysaccharides with CRC inhibitory actions from various plants, including Dendrobium officinale Kimura et Migo., Nostoc commune Vaucher, and Ganoderma lucidum (Leyss. ex Fr.) Karst. The novel founded mechanisms mainly include: inhibiting cancer cell proliferation by acting on IRS1/PI3K/Akt and IL-6/STAT3 pathways; inducing cancer cell apoptosis by acting on LncRNA HOTAIR/Akt mediated-intrinsic apoptosis, or regulating the TNF-α-mediated extrinsic apoptosis; inducing cancer cell autophagy by acting on endoplasmic reticulum stress or mTOR-TFEB pathway; inhibiting cancer cell metastasis by regulating Smad2/3 and TLR4/JNK pathways; regulating TME in CRC; and maintaining the intestinal barrier. This review will provide more novel research strategies and a solid literature basis for the application of polysaccharides in the treatment of CRC. [ABSTRACT FROM AUTHOR]

Trichothecium roseum is an important postharvest pathogenic fungus. Within its molecular framework, the epigenetic reader Snt2 emerges as a key player, capable of modulating fungal growth, development, autophagy, and pathogenicity. However, the role of TrSnt2 in regulating autophagy, reactive oxygen species (ROS) accumulation, ergosterol synthesis, and the pathogenicity of T. roseum remains unexplored. In this study, we showed that Trsnt2 deletion increased the acetylation level of H3 and simultaneously upregulated the expression of 15 autophagy genes (Atg1 , 2 , 5 , 8–14 , 16 , 18 , 20 , 22 , 24), thereby promoting autophagosome formation and mitophagy in T. roseum mycelia. Remarkably, Trsnt2 deletion exerted a dual effect on ROS dynamics: it downregulated the expression of ROS production-related genes (NoxA , NoxB , and SOD), while also dampening the expression of ROS scavenging-related genes (CAT , CTT1 , POD , APX , GPX , and TrxB), ultimately resulting in decreased ROS accumulation in the mycelia. Furthermore, Trsnt2 deletion orchestrated a shift in the expression profile of genes associated with the late pathway of ergosterol synthesis (Erg2 , Erg3 , Erg5 , and Erg6) in addition to the downregulation of Erg4. This cascade of events led to significant membrane damage and subsequent cell death. Furthermore, the effect of Trsnt2 deletion extended to the pathogenicity of T. roseum on muskmelon and tomato fruit, where a reduction in pathogenicity was observed. In conclusion, Trsnt2 emerges as a critical regulator in shaping T. roseum pathogenicity on fruit, orchestrating a complex interplay of cellular processes. • Trsnt2 deletion promoted autophagosome formation and mitophagy in mycelia. • Deletion of Trsnt2 reduced ROS levels, leading to membrane damage and cell death. • Trsnt2 deletion reduced the pathogenicity of T. roseum on muskmelon and tomato fruit. [ABSTRACT FROM AUTHOR]

To address the molecular mechanisms underlying macrophage migration inhibitory factor (MIF) induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration and vascular remodeling in pulmonary hypertension (PH), primary cultured rat PASMCs and monocrotaline (MCT)-induced rats with PH were applied in the present study. The results showed that MIF increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, and then stimulated activating transcription factor 6 (ATF6) activation, subsequently triggered autophagy activation, which further led to programmed cell death factor 4 (PDCD4) lysosomal degradation, and eventually promoted PASMCs proliferation/migration. In lung tissues of MCT rats, MIF protein expression was elevated, phosphorylation of STAT3 and activation of ATF6 were increased, activation of autophagy was evident, and reduction of PDCD4 was observed. Intervention with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP), ATF6 blocker melatonin or autophagy inhibitor chloroquine, confirmed the in vitro interaction among MIF, STAT3, ATF6, autophagy and PDCD4 in MCT induced rats with PH. Targeting MIF/STAT3/ATF6/autophagy/PDCD4 axis effectively prevented the development of PH by suppressing PASMCs proliferation and vascular remodeling. In conclusions, we demonstrate that MIF activates the STAT3/ATF6/autophagy cascade and then degrades PDCD4 leading to PASMCs proliferation/migration and pulmonary vascular remodeling, suggesting that intervention this axis might have potential value in management of PH. [ABSTRACT FROM AUTHOR]

Hematotoxicity of benzene is derived mainly from its active metabolite, 1,4-Benzoquinone (1,4-BQ), which induces cell apoptosis and mitochondrial damage. Damaged mitochondria are degraded through a specialized autophagy pathway, called mitophagy, which is driven by PINK1/Parkin signaling. However, whether mitophagy is involved in 1,4-BQ-induced toxicity remains unclear. This study was designed to investigate whether PINK1/Parkin-mediated mitophagy is activated in 1,4-BQ-treated HL-60 cells, and the roles mitophagy plays in 1,4-BQ-induced apoptosis. Our results demonstrated that 1,4-BQ induced autophagy in HL-60 cells, characterized by increased LC3-II/LC3-I ratio and Beclin1 expression, as well as decreased expression of p62. We confirmed the presence of mitophagosomes using electron microscopy, and found that 1,4-BQ-induced autophagy was blocked by pretreatment with the mitophagy inhibitor Cyclosporine A (CsA). In addition, we found that 1,4-BQ induced mitochondrial stress through decreased mitochondrial membrane potential (MMP) and increasedproduction of reactive oxygen species (ROS). We also confirmed that 1,4-BQ-induced mitophagy was mediated by the PINK1/Parkin pathway, illustrated by increased expression of PINK1 and Parkin mRNA and protein. Finally, we examined 1,4-BQ-induced apoptosis with or without CsA, which demonstrated that apoptosis increased after mitophagy inhibition, suggesting that mitophagy has a protective effect in this context. In conclusion, this study demonstrates that the activated PINK1/Parkin-mediated mitophagy exerts a significantly protective effect against 1,4-BQ-induced apoptosis in HL-60 cells. [ABSTRACT FROM AUTHOR]